Release Ca from intracellular stores Ca CHANNEL BLOCKERS ANTIANGINAL DRUGS Dihydropyridines:- Nifedipine , Nicardipine, Amlodepine Phenylalkylamines:- Verapamil Benzthiazepines:- Diltiazem Classification Heterogeneous MLCK P MLC Active form Contraction Actin Ca2+ CaM complex Release Ca from intracellular stores Ca2+ CaM Kinase Phosphatase Mechanism Binding of calcium channel blockers [CCBs] to the L-type Ca channels  their frequency of opening in response to depolarization Verapamil Nifedipine Diltiazem X entry of Ca   Ca from internal stores  No Stimulus-Contraction Coupling  RELAXATION Relaxation

Cardiac & VSMCs / neurons Cerebellar Purkinje neurons Ca CHANNEL BLOCKERS Ca Channel Types & Distribution Pharmacodynamic Actions Distribution Type Cardiac & VSMCs / neurons L Heart / neurons T Neurons N Cerebellar Purkinje neurons P 1. Anti-Anginal Actions Verapamil Nifedipine Diltiazem  Cardiomyocyte Contraction cardiac work through their –ve inotropic & chronotropic action (verapamil & diltiazem)  myocardial oxygen demand VSMC Contraction  After load  cardiac work  myocardial oxygen demand Coronary dilatation (nifedipine & nicardipine (short acting) / amlodipine (long acting) > diltiazem & verapamil  myocardial oxygen supply N.B. Selectivity of Ca channel blockers Nifedipine  VSMCs Verapamil  Cardiomyocytes > VSMCs Diltaizem  Intermediate action on both

Ca CHANNEL BLOCKERS Indications AS ANTIANGINAL IN STABLE ANGINA; Regular prophylaxis  Long acting dihydropyridines ; amlodipine & SR formulation nifedipine, diltiazem > verapamil Short acting dihydropyridine avoided  BP symathetic activation refelx tachycardia +syncope impair coronary fillingischemia ….. Can be combined to b-AR blockers??? Which group is much safer???  Can be combined with nitrates??? Which group is much safer???  Dihydropyridenes  no  contractility  useful antianginal if with CHF  Verapamil & diltiazem  < vasoactivity  as antianginal if hypotension IN VARIANT ANGINA Attacks prevented (> 60%) / sometimes variably aborted IN UNSTABLE ANGINA; Seldom added in refractory cases

ANTIANGINAL DRUGS K CHANNEL OPENERS Nicorandil Mechanism It has dual mechanism of action; 1. Opens KATP channels (> arteriolar dilator) 2. NO donner as it has a nitrate moiety (> venular dilator) Pharmacodynamic L 1. On VSMC K channel opening  Hyperpolarization VASODILATATION 1. On Cardiomyocyte Nicorandil K channel opening  Repolarization Cardiac work Inhibit Ca entry 1.Opening of KATP channels

K CHANNEL OPENERS NO donner   cGMP/ PKG VASODILATATION Indications Nicorandil K CHANNEL OPENERS 2. Acting as NO donner 2. On VSMC NO donner   cGMP/ PKG VASODILATATION Indications Prophylactic 2nd line therapy in stable angina & refractory variant angina Flushing, headache, Hypotension, palpitation, weakness Mouth & peri-anal ulcers, nausea and vomiting. ADRs

DRUGS USED IN TREATMENT OF ANGINA b – AR BLOCKERS

VSMC SMC CARDIOMYOCYTE b - AR BLOCKERS  Cardiac Work B1 B2 NO Vasodilatation VSMC SMC B2 CARDIOMYOCYTE B1  Cardiac Work b1 – Selective > Non – Selective NO Relaxation Atenolol Bisoprolol Metoprolol Pharmacodynamic Actions 1. Anti-Anginal Actions cardiac work through their -ve inotropic & chronotropic action afterload renin angiotensin release  myocardial oxygen demand Though no coronary dilatation, yet  prolonged diastole   perfusion time   coronary filling & flow  myocardial oxygen supply

ANTIANGINAL DRUGS b - AR BLOCKERS Indications as antianginal IN STABLE ANGINA; Regular prophylaxis  Cardio-selective are better. Why???  to spare b2-AR They are 1st choice on prolonged use   incidence of sudden death specially due to ventricular tachycardia  by their antiarrhythmic action. Can be combined with nitrates  abolish its induced reflex tachycardia. Can be combined with dihydropyridene CCBs but not verapamil nor diltiazem  for fear of conduction defect (bradycardia, heart block) IN VARIANT ANGINA contraindicated  as it has no vasodilator action & allow unopposed -adrenergic coronary vasoconstriction to occur. IN UNSTABLE ANGINA  halts progression to AMI  improve survival In Myocardial Infarction; given early  infarct size, morbidity & mortality  CARDIOPROTECTIVE  myocardial O2 demand.  Redistribution of blood flow in the myocardium. free fatty acids. Anti-arrhythmic action.  incidence of sudden death.

b - AR BLOCKERS Precautions - blockers should be withdrawn gradually as sudden stoppage  give rise to a withdrawal manifestations: Rebound angina, arrhythmia, myocardial infarction & hypertension WHY ?  Up-regulation of -receptors. Non-selective are better avoided as they blocks vasodilatory effects of sympathetic stimulation  afterload &  oxygen consumption. Not used in variant angina  worsen symptoms and aggrevate condition Given to diabetics with ischemic heart disease  [Benefits > hazards) & ACE inhibitor must too be added specially in ACSs

Metabolically acting agents DRUGS USED IN TREATMENT OF ANGINA Metabolically acting agents

X ANTIANGINAL DRUGS Metabolically Acting Agents TRIMETAZIDINE Mechanism O2 requirement for glucose utilization is < FFA utilization i.e. oxidation of FFA requires > oxygen per unit of ATP generated than oxidation of CHO. During ischemia, metabolism shifts to oxidation of FFA. So, to treat we can enhance > utilization of CHO (less energy cost) ; by giving  Partial FFA Oxidation Inhibitors (pFOX Inhibitors), TRIMETAZIDINE 3KAT Pharmacol Effects Restores energy balance in the cell.  fatty acid metabolism by -ve 3 Ketoacyl Thiolase [3KAT] -ve anaerobic glycolysis X Allowing only aerobic glycolysis -ve acidosis & FR accumulation   apoptosis  Cytoprotective Thus shift myocardial metabolism to  OXYGEN DEMAND WITHOUT ALTERING HEMODYNAMICS

Metabolically Acting Agents Indication Used when ever needed as add on therapy to nitrates, CCBs or b-blockers ADRs  GIT disturbances Contraindications Hypersensitivity reaction In pregnancy & lactation Ranolazine Newly introduced. Considered one of the metabolically acting agents like trimetazedine. + affects Na dependent-Ca Channels  prevents Ca load   apoptosis  cardioprotective. It prolongs the QT interval so not given with; Class Ia & III antiarrhthmics Toxicity develops due to interaction with CYT 450 inhibitors as; diltiazem, verapamil, ketoconazole, macrolide antibiotics, grapefruit juice

X DRUGS USED IN TREATMENT OF ANGINA OTHERS OTHERS Ivabradine SAN Not classified  claimed to be CARDIOTONIC agent X SAN Acts on the “ Funny Channel” a special Na channel in SAN HRmyocardial work Myocardial O2 demand OTHERS

Agents that improve prognosis DRUGS USED IN TREATMENT OF ANGINA Agents that improve prognosis Aspirin / Other antiplatelets Statins ACE Inhibitors -AD blockers Main Stay of Prophylactic Treatment Halt progression Prevent acute insults Improve survival

ANTIANGINAL DRUGS SET THE BALANCE BACK  In attack & situational prophylaxsis Short acting nitrates For prophylactic therapy β-adrenoceptors blockers. Calcium channel blockers Long - acting nitrates. Potassium channel openers Metabolic modifiers & others In Combinations

THERAPEUTIC GUIDELINES FOR ISCHEMIC HEART DISEASES Stable Angina: Acute symptoms by short acting nitrates Maintain therapy by a suitable antianginal drug (Nitrates and/or β- Blockers and/or CCB + metabolic modifiers). Vasospastic Angina: Prevention and even abortion of an attack of coronary artery spasm is achieved by Nitrates and/or CCB. Propranolol is contraindicated. ACS Unstable angina:  Better transfer to ICU or CCU. Antianginal drugs (Nitrates &/or B-blockers, CCB in refractory cases) + Aspirin or Antiplatelets & IV Heparin. IF THERAPY FAIL to any REVASCULARIZATION ?  OPENING OF OCCLUDED VESSEL either by; Percutaneous coronary intervention; PCI Surgical coronary artery bypass grapht; CABG

AMI: Transfer to CCU & apply the following measures: ACS AMI: Transfer to CCU & apply the following measures:  Before & During Transfer: Cardiopulmonary resuscitation / Oxygen & I.V fluids. Nitroglycrine sublingual up to 3 doses with 5 minutes intervals Analgesics, as morphine, for severe pain. Chewable aspirin 160 mg. In ICU or CCU units: Thrombolytics: to induce clot lysis & restore blood flow Anti-coagulant: IV Heparin, continue on aspirin orally O2 & Opiates: IV morphine or meperidine. Nitrates: IV infusion of GTN + early b-blockers  myocardial damage. ACE Inhibitors start early postmyocardial fibrosis & improve survival Statin therapy start early stabilize plaque

GOOD LUCK

Neutrophilic Infiltrate SEQUENCE OF EVENTS AFTER AMI Coagulative Necrosis Neutrophilic Infiltrate After 1 day < 3days Granulation T. Scaring & Fibrosis 1-2 weeks >3 weeks Benefits of adding ACE Inhibitors & b-blockers Post-myocardial Fibrosis

PCI + STENT DEPLOYMENT Ballon Angioplasty

Case A60-year-old man comes into the office complaining of chest pains that primarily occur in the early morning and do not appear to be associated with stress or exercise. Following coronary angiography and a positive ergonovine test you determine that this patient has angina pectoris as a result of coronary artery spasm. Ergonovine test performed if angina is thought to be caused by coronary artery spasm. The procedure is conducted during coronary angiography. The artery-narrowing drug ergonovine (or, alternatively, acetylcholine) is injected to provoke coronary artery spasm. If the individual experiences severe arterial spasm in response to ergonovine, he or she probably has variant angina.

Q1 How would you treat the patient to alleviate the acute attacks when they occur ? Treat the patient with sublingual nitroglycerin for the acute attacks because of its rapid onset of action and its powerful vasodilating effect on the large epicardial conductance coronary arteries, which are normally the primary site of the spasm

How would you treat chronically to prevent their reoccurrence? Q2 How would you treat chronically to prevent their reoccurrence? For the chronic treatment there are two possibilities, an oral calcium channel blocker, such as amlodipine or verapamil, or a long-acting nitrate preparation, such as the transdermal form of nitroglycerin given once a day at bedtime to prevent the early morning episodes. -Adrenoceptor blockers are not used for patients with coronary vasospasm, as they may worsen the condition.